The unifying goal of this program project proposal is to define the principles governing normal nervous system developmental processes that may lead to brain dysfunction and mental retardation. The studies for the most part are basic in nature, focussing on various aspects of the cell and its environment that are involved in overall developmental processes; including examination of the extracellular matrix (ECM), cell surface components and possible external signals which provide the milieu for cell differentiation an proliferation. The derivative information from these proposed studies should define specific loci where normal developmental processes may be interrupted by external influences (soluble factors, cell surface or ECM components) leading to abnormal nervous system development and mental retardation. In Project II, the structure and function of two chemically, immunologically and developmentally distinct proteoglycans (PG) and their putative role will be examined in normal brain and in a mouse mutant exhibiting hydrocephalus. In Project VII), the structure, function and regulation of cranin, a laminin-binding protein of cell membranes will be characterized. As well, behavior and physiologic studies will be pursued of rapid onset neurites in NG-108-15 cells in order to define more precisely how living neural cells respond to laminin. In Project (X), combination of biochemical, immunocytochemical and electrophysiological methods will be pursued to study the regulation and function of calcium channels in bovine adrenal chromaffin cells and the mechanisms by which neurotransmitters activate calcium channel facilitation in these cells. In addition, mechanisms by which insulin-like growth factor-I(IGF-I) increases calcium uptake and catecholamine secretion in chromaffin cells will be investigated. In Project XI, the biochemical and molecular basis for the importance of the cholinergic and enkephalinergic systems in the developing central nervous system at two distinct biological periods, during neuronal proliferation and neuronal differentiation will be established. A comprehensive multi-disciplinary approach using biochemical, pharmacologic, morphologic and cell culture techniques with expanding emphasis on molecular approaches will be used in all four projects. The derivative information from these proposed studies should define specific loci where normal developmental processes may be interrupted by external influences (soluble factors, cell surface or ECM components) leading to abnormal nervous system development and mental retardation.